The mammalian cortex is specialized to allow integration of sensory inputs with emotional context and memory to promote behavioral output. The interplay between the subcortical reward circuits, prefrontal cortical areas controlling motivation and hippocampal regions required for learning all contribute to how humans interact with the world and also are key parts of the circuitry of addiction. Addiction as a syndrome is essentially a subversion of the normal functions of the cortex and circuit plasticity leading to maladaptive behaviors. In order to understand the developmental underpinnings of addiction it is necessary to ultimately understand the cues that regulate the development of the various building blocks of the addiction circuit. The construction of the cerebral cortex requires complex orchestration of progenitor proliferation, patterning, neuronal differentiation, migration and axon guidance in order to generate the building blocks of cortical circuitry. Much attention has been paid to signaling molecules produced within the developing cortex that govern these events, but I have been fascinated by signals produced by the mesenchymal cells covering the cortex (the meninges) that we've shown regulate several key events during cortical development. During the entire period of corticogenesis the neuroepithelial stem cells and radial glia as well as many radially and tangentially migrating neurons have intimate physical association with the meninges. Because of this close physical association, several years ago I wondered whether the meninges modulate cortical development in an instructive manner. Following this idea we have identified a series of secreted factors made by the meninges that influence cortical development. These studies were the subject of the last funding cycle for this award. The primary hypothesis of this competitive renewal is that Bmps produced by the meninges regulate radial migration and lamination of cortical neurons. Furthermore we will test the idea that Bmps control radial migration by regulating the behavior of the leading process of migrating neurons via regulation of actin dynamics using the actin modulating protein cofilin. This work will dramatically expand our understanding of the molecular control of cortical development, will help to reveal the basis of a variety of developmental malformations of the cortex and will provide novel insights into the cellular regulation of radial migration in the cortex.
Aim 1 : Determine how meningeal Bmp7 regulates cortical lamination and radial migration.
Aim 2 : Characterize the interaction between Bmp signaling and cofilin phosphorylation in regulating radial migration in the cortex.
In recent years it has become apparent that cortical development and function are related to many of the things that make us most human - emotion, drive and impulsivity - and also to a variety of disorders like autism, epilepsy and addiction. Despite the fundamental importance of cortical development there remain major questions about the key regulatory events that shape the formation of the brain. In this proposal we continue to explore our recent hypothesis that the meningeal coverings of the brain play fundamental roles in the development of the cortex.
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